title: LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.
abstract: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Bailey
authors.forename: Jason P
authors.initials: JP
authors.lastname: Covy
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.forename: Linda
authors.initials: L
authors.lastname: Rousseau
authors.forename: Ruth
authors.initials: R
authors.lastname: Watkinson
authors.forename: Joshua
authors.initials: J
authors.lastname: Knight
authors.forename: Sarah
authors.initials: S
authors.lastname: Miles
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000939:Epitopes; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases